The major goal of this research will be to develop the synthetic, computer assisted molecular modeling, and biophysical methods that will allow us to develop the lead anticancer peptides obtained from the random library synthesis and screening processes of this NCDDG into lead drug candidates that will have the appropriate biological activities and selectivities, stabilities and biodistribution properties. Particular emphasis will be placed on improving pharmacological, physiological and therapeutic profiles. To accomplish these broad objectives will require continued development of several different but related specific aims including: 1) development of synthetic chemistry especially asymmetric synthetic and macrocyclic cyclization methods that can be used on the design and synthesis of specific peptides and pseudopeptides; 2) design of specific conformational and topographical constraints into peptides; 3) development of appropriate purification methods and analytical tools to evaluate unique structures; 4) examine the conformational and topographical properties of key lead peptides using state of the art 2D NMR and other biophysical methods including computational chemistry and molecular mechanics and molecular dynamics calculations. The results from these studies will be evaluated in conjunction with extensive biological studies by our colleagues on this NCDDG and used as necessary in conjunction with computer assisted design to develop new and better antitumor analogues for drug development. The long term goal of this work is to develop new and more effective drugs for the treatment of cancer.